Its screen for selected variants of some disease-linked genes gives customers an incomplete picture of their risk—do they know?

Jul 9, 2019

When MyHeritage’s chief scientific officer Yaniv
Erlichannounced the launch of the company’s new Health+Ancestry test on Twitter earlier this
summer, the feedback wasn’t entirely positive.

The array-based screen offering insights into a customer’s genealogical and health background from a cheek swab
is a rival to 23andMe’s service of the same name. It promises risk reports for genetic variants
associated with conditions including breast cancer and heart disease, and, unlike 23andMe, provides conversations
with a genetic counselor, should the test turn up anything concerning—all for the price of $199 plus shipping.

But, as some Twitter users were quick to point out, the company’s 5,000-word blog post on the product was thin on medical specifics.
‏‏“Your blog brags that it tests for, ‘hereditary BRCA cancers (for which we support more
variants than our major competitor),’” tweetedKyla Dunn, a genetic counselor at the Stanford Center for
Inherited Cardiovascular Disease, on May 21. “Can you please provide a LIST OF THE VARIANTS . . . so the
biomedical community can better understand the limitations of this new, inadequate test marketed directly to
consumers.”

We know that our test isn’t comprehensive.

—Yaniv Erlich, MyHeritage

As for many disease-related genes, there are thousands of variants of BRCA1 and BRCA2, most of
which are rare in any given population, and many of which are caused by the sort of mutations—large deletions
or insertions, for instance—that are undetectable with an array-based test. Some variants are pathogenic,
meaning they’re associated with an increased risk of disease—typically cancers such as breast or ovarian
cancer—although many other genetic and environmental factors interact to influence the outcome. A negative
test result for one variant, particularly if that variant is rare in the population being tested, offers negligible
information about the overall risk of developing cancer.

When 23andMe received market authorization last year for its “BRCA (selected
variants)” test, which it added to a list of tests for variants associated with other medical conditions, it
kicked up a storm in the medical community. Physicians and genetic counselors reported cases in which patients had
misunderstood their test results—overestimating the seriousness of a positive result, for example, or
underestimating their risk of disease after a negative result. 23andMe’s BRCA test covered just three
single-nucleotide polymorphisms (SNPs) that principally affect women of Ashkenazi Jewish descent, rendering the
results uninformative about disease risk to the vast majority of the population.

On May 22, following some back-and-forth over Twitter, Erlich tweeted a list of 13 BRCA variants that MyHeritage offers testing for—still
just a fraction of the variants associated with disease risk. Erlich tells The Scientist that the
company’s test should currently be able to identify almost half of people carrying potentially deleterious
mutations in BRCA1, and a third of those with mutations in BRCA2—almost double
23andMe’s statistics, he notes.

At the time of this article’s publication, the variant information isn’t listed on the company’s
website—an omission that Erlich notes is due to a delay in website design rather than a lack of transparency.
“There is no secret—it’s just that we didn’t have time to put it on the webpage,
basically,” he says. “When people get the results, they’ll see all the variants that were tested,
all the technical information, and so on.”

The omission of variant information, which also applies to the other polygenic
conditions the company tests for, isn’t the only detail to raise medical professionals’
eyebrows. Researchers who spoke to The Scientist highlighted other aspects of MyHeritage’s move into
health-related genetic testing—from the company’s approach to regulatory oversight, to the language in
its marketing materials—that heighten their concerns about this minimally regulated marketplace, and the risks
it presents to consumers.

A regulatory blind spot?

Founded in 2003, MyHeritage now has more than 110 million registered users, who can use the company’s platform
to create family trees, share photos, and explore their ancestry via online historical records. The company began
offering ancestry-related DNA testing in 2016 to customers interested in learning more about their
past, and currently holds DNA data for more than 3 million users. According to a recent report by MIT Technology Review, it now has the third largest
repository of customer DNA, after Ancestry.com’s 14 million customers (who can only access ancestry-related
tests) and 23andMe’s 9 million or so (for whom ancestry and health analyses are available).

Although MyHeritage’s latest product bears many similarities to that of its rival, there are some key
distinctions in how the company offers access to particular variant tests—several of which have implications
for its relationship with regulators.

While 23andMe’s service is a true direct-to-consumer test, as customers order the product themselves,
MyHeritage involves an intermediary step as part of what the company refers to as “physician oversight.”
In practice, this means that, after purchasing a Health+Ancestry kit but before receiving the results, a customer
fills in a questionnaire about his medical history for review by a physician at telemedicine firm PWNHealth.

The physician uses the answers to identify any conditions for which a customer has a particularly high risk, and
MyHeritage then withholds reports on variants related to that particular condition. For example, Erlich explains,
“if you indicate that you [or your family] have a history of breast cancer . . . which means that you are high
risk to carry a BRCA mutation, you are not eligible to get this report.” Such a person would then be
encouraged to speak to her health care provider to see whether she should get more thoroughly tested.

I think if it’s done well, thoughtfully, carefully, then that is perfectly appropriate.

—Robert Green, Brigham and Women’s
Hospital

This extra step allows MyHeritage (and a handful of smaller companies taking a similar approach) to address a key
concern about direct-to-consumer genetic testing, Erlich says—that people with a known high risk for a certain
condition might mistakenly view selected-variants tests as a substitute for getting properly screened. “We
know that our test isn’t comprehensive,” he explains. Customers will still be able to get reports on
variants related to conditions for which they haven’t reported risk factors, he adds.

There’s another consequence of physician involvement, though: it has allowed MyHeritage to avoid the sort of
regulatory oversight associated with traditional direct-to-consumer products such as 23andMe’s. As US Food and
Drug Administration (FDA) press officer Megan McSeveney explains in an email to The Scientist, the FDA historically
hasn’t required companies to seek regulatory authorization for genetic tests “if they are offered to
patients only when prescribed or ordered by a health care provider”—a policy “premised on the
presence of physician assistance and oversight.”

Steven Woloshin, a codirector of the Center for Medicine and Media at The Dartmouth
Institute, notes that the agency originally adopted this discretionary approach to physician-mediated tests so that
it wouldn’t interfere in one-off, laboratory-developed tests (LDTs) that doctors order for individual patients
to answer specific questions in a medical setting. Those tests “weren’t meant to be marketed on a large
scale,” he says, so premarket review wasn’t a priority.

But some mass-marketing companies may now be exploiting this “loophole” to sidestep regulation, he says.
He highlights the story of Kailos Genetics, a small, Alabama-based company that received a violation letter
in 2015 from the FDA for marketing unapproved, health-related genetic tests directly to consumers. Soon after, the
company added a physician-oversight step to its procedure. “Now, they’re able to sell exactly
the same unapproved test,” Woloshin says, “because a physician order is required.”

Erlich did not directly respond to a question about whether the regulatory situation played a role in
MyHeritage’s decision to include physician oversight, but writes in an email to The Scientist that he
disagrees with the idea that getting physicians involved amounts to “exploiting a loophole.” Oversight
of LDTs via telemedicine “is a rapidly growing segment in health care,” he says. Noting that
23andMe’s test doesn’t offer such oversight, he says that “all in all, I feel much better with our
approach.”

There are signs that regulators are paying attention to the medical community’s concerns about how
health-related genetic testing is presented to customers. FDA’s McSeveney, for example, notes that
“Congress is considering possible legislation regarding regulation of in vitro clinical tests,”
including the sort of tests used by MyHeritage and other personal genetic testing companies—a move that
researchers who spoke to The Scientist suggest is partly a result of the way some companies have employed
physician oversight.

Robert Green, a medical geneticist at Brigham and Women’s Hospital and Harvard Medical
School, as well as a consultant for a number of genetic testing companies, notes there’s a spectrum of
behavior in how companies make use of physician involvement. “I do have a problem with companies that are
simply using physicians as a workaround so they don’t have to get FDA approval,” says Green, who
cofounded Genome Medical, a telemedicine company focusing on genetic health information, in 2016.

But, he says, if a physician’s input is used for “prescreening, not necessarily in person, [to] flag
people for whom this is not the appropriate test,” then it allows companies to provide a better service.
“I think if it’s done well, thoughtfully, carefully, then that is perfectly appropriate.”

Mixed messaging

Physician oversight may help companies mediate what information is provided to people with particularly elevated
health risks. But it can’t identify everyone who will go on to test positive for disease-related risk
variants, nor does it guarantee that people will be able to interpret the results of selected-variants tests when
they receive them. (MyHeritage offers genetic counseling to customers only in certain circumstances—for
example, when a report indicates that they have an elevated disease risk.) As a result, some researchers are
concerned that this extra safeguard does little to reduce customer confusion.

The situation might not be helped by the products’ presentation on company websites. For instance, language
near the bottom of the product page for MyHeritage’s Health+Ancestry test explains that “the new health
product is not intended . . . for making medical decisions,” and that “users may need to obtain further
services from their physician, a genetic counselor, or other healthcare provider, in order to obtain diagnostic
results regarding the conditions or diseases indicated within the MyHeritage DNA health reports.”

This isn’t just a patient confusion issue; providers are really confused by it too.

—Susan Domchek, Perelman School of
MedicineUniversity of Pennsylvania

At the top of the same page, however, MyHeritage says that its Health+Ancestry test “offers new dimensions of
genetic insight to enrich your life, enlighten you about your health, and help you make informed lifestyle
choices.” The 23andMe website describes its product in similar terms, and CEOs from bothcompanies have referred to their work as part of a movement to
“democratize health care.”

“This language is ridiculously confusing,” says Susan Domchek, a medical oncologist at the University of Pennsylvania’s Perelman
School of Medicine who wrote in STATlast year about her experiences with
patients who’d received results from selected-variants tests. Doctors don’t usually consider selective,
array-based tests—as opposed to a full scan of a person’s gene sequences—to be enlightening about
a patient’s risk of complex health conditions such as breast cancer, she adds, so it’s not clear what
people should do with the results they receive. “This isn’t just a patient confusion issue; providers
are really confused by it too.”

Woloshin also finds some of the product descriptions “pretty fishy,” he says, adding that regulators
typically pay less attention to the marketing claims of companies that haven’t been required to pursue
premarket review. “The question is: What do consumers understand? What’s the impression that a consumer
gets when they see this sort of language?”

There’s little research on how consumers perceive companies’ marketing materials for health-related
selected-variants tests, but advocates of such testing dispute the idea that consumers misinterpret what’s on
offer. A comprehension survey that Erlich’s team carried out on a “representative sample of 100
people,” for example, found that each question was answered correctly by at least 90 percent of respondents,
demonstrating that most people have a good understanding of the principles behind the company’s product, he
tells The Scientist.

And research
carried out a few years ago by Green and colleagues found that, of more than 1,500 people who had already taken a
health-related, array-based test such as 23andMe’s, just 2 percent expressed regret about their decision to
take the test, while 1 percent reported that the decision had “done them harm.” (That study also found
that nearly 40 percent of respondents had given no thought before purchasing the test to whether they might receive
unwanted results.)

Green notes that there’s now a huge amount of available information about health-related genetic tests, both on
company websites and in the press, so people are alerted to the implications of taking such a test before they buy.
He adds that “it’s tough for a business to market its own limitations to its customers,” but that
most responsible businesses do state their products’ caveats, albeit “in a way that doesn’t debase
the whole product.”

Clarification (July 15): The article has been updated to reflect the fact that the MyHeritage website only omits
variant information for polygenic conditions. A company spokesman notes that specific variant information is available on the site for
monogenic conditions.